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Review Article
The role of taxanes in the management of gastroesphageal cancer
11Department of Oncology, National Cancer Institute, Bogotá, Colombia; 2Department of Gastrointestinal Medical Oncology, The University of Texas MD
Anderson Cancer Center, Houston, Texas, USA
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Abstract
Upper gastrointestinal cancers commonly referred to as gastroesophageal carcinomas encompass cancers of the esophagus,
stomach and gastroesophageal junction. Although the number of newly diagnosed cases of gastric cancer has decreased
in the United States, the whole burden of upper gastrointestinal carcinomas on society remains significantly high,
with only a small improvement in overall survival achieved over the past two decades. Traditionally, therapeutic agents
used to treat gastroesophageal cancers have been platinums and fluoropyrimidines. Taxanes are di-terpenes produced
by the plants of the genus Taxus (yews). As their name suggests, taxanes were first derived from natural sources, but now
they are all synthesized artificially. Interfering with cellular microtubular function during cell division is the main mechanism
of action for currently available taxanes. Since their introduction into therapeutic oncology, many different other
taxane-derivatives have been manufactured and are being developed. Changing the formulation of the drug to improve
delivery such as liposomal encapsulation, and target deliver with antibody-drug conjugation, as well as introducing new
class of cytotoxic agents that can overcome taxane-resistance. The two most commonly used taxanes are paclitaxel and
docetaxel. Taxane is a class of cytotoxic agents more commonly administered in patients with breast and lung cancers.
However, the regulatory approval of docetaxel to treat patients with metastatic or advanced gastroesophageal cancers in
2006 established the role of taxanes in the management of upper gastroesophageal cancers. This paper will review the
current data of taxanes in the management of patients with upper gastrointestinal cancers.
Key words
taxanes, gastric, esophageal, gastroesophageal junction, chemotherapy
J Gastrointest Oncol 2011; 2: 240-249. DOI: 10.3978/j.issn.2078-6891.2011.027
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Introduction
Upper gastrointestinal cancers , also refer to as
gastroesophageal carcinomas (GECs) consist of cancers
of the esophagus, stomach and gastroesophageal junction
(GEJ). GECs are the fourth most frequently diagnosed
cancer worldwide, and they are the second most common
cause of cancer-related mortality (1). Since the late 1990s, the anatomic location of upper gastrointestinal
carcinomas has shifted and this anatomic shift has varied
geographically. In most Western countries, there has been
an epidemiological shift: there has been a decrease in the
incidence of GECs, but a steady increase in the incidence
of cancers of the gastroesophageal junction (GEJ) (2,3).
Over the past 10-15 years, the anatomic primary site of
upper gastrointestinal carcinomas in the West has shifted to
the GEJ (2). An explanation for this phenomenon remains
elusive, but speculation is that environmental factors
common in Western countries, particularly the higher
frequency of obesity, gastroesophageal reflux disease, and
Barrett’s esophagus, are the likely culprits. On the other
hand patients in Eastern countries with a high prevalence
of GECs, GECs are still primarily located in the distal
gastrum and proximal esophagus (1). Complete surgical
resection remains the only treatment option for long-term
disease control and cure. However, because of the high rate of recurrence and the inaccuracy of clinical staging, surgery
alone is associated with a 5-year overall survival (OS) rate of
only 20-30% (4,5). Multimodality therapy with concurrent
chemotherapy, chemoradiotherapy (CRT), or both is
commonly used to improve the duration of disease-free
survival after complete surgical resection. Several recent
randomized trials have shown improved survival outcomes
when surgery is combined with another therapy (4-7).
Unfortunately, more than 50% of newly diagnosed GECs
are locally advanced (unresectable) or metastatic at the time
of diagnosis. Among patients presenting with locoregional
disease, less than 30% will have potentially resectable
disease (8).
Randomized controlled trials have reported that a
statistically significantly survival benefit can be attained
with chemotherapy plus supportive care compared with
supportive care alone, even in patients with locally advanced
(unresectable) or metastatic GECs (9). However, patient
selection is crucial to enhance the potential survival benefit
in patients with advanced GECs. Antimetabolites, such as
methotrexate, and alkylating agents, such as mitomycin,
were a mainstay of early therapy for advanced GECs. While
these agents remain important in the treatment of patients
with other malignancies, their narrow therapeutic index
of significant side effects and minimal improvement of
outcomes, minimize any potential benefit for patients with
advanced GECs. Until 2000, the only chemotherapeutic
agents approved by the U.S. Food and Drug Administration
(FDA) for the treatment of GECs included platinums
(cisplatin, carboplatin), anthracyclines (doxorubicin,
epirubicin), and pyrimidine analogs (5-fluorouracil [5-FU]).
During that time span, treatment with chemotherapy
resulted in only marginal survival improvement for patients
with GECs (10). The combination of limited therapeutic
options and narrow therapeutic indices of available agents
resulted in disappointing treatment outcomes in patients
with GECs. Until mass screening programs for GECs
become available in Western countries, such as those
already available in Japan, most GECs will continue to be
diagnosed at more advanced stages. Overall, the prognosis
of patients with GECs is poor, and it is particularly dismal
for those with unresectable disease. To improve surgical
outcomes or meaningful survival benefits, new effective
cytotoxic or biologic targeted systemic therapies are needed
for both resectable and unresectable or metastatic GECs.
Since 2006, the FDA has added a new indication for
GECs to several cytotoxic agents. The main benefit of
modifying older cytotoxic agents is an improved toxicity
profile; examples of modified cytotoxic agents include
oxaliplatin, which is a third-generation platinum, and
capecitabine and S-1, which are modified or newer formulations of 5-FU. Prior to 2007, paclita xel and
docetaxel were already being used to treat patients with
other solid tumor malignancies, but they did not have an
FDA-approved indication for treating patients with GECs.
In this paper, we will review the current roles taxanes in the
management of GECs and discuss the future directions of
their use.
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Taxanes
Paclitaxel and docetaxel belong to the Taxane family
because of their chemical structures contain a common
three phenols ring. The clinical application of taxanes in the
management of GECs predates their approval by the FDA
for such an indication. It was not until 2006 that docetaxel
received FDA approval for use as a first-line treatment in
therapy-naïve patients with advanced GECs (11).
Taxanes are di-terpenes produced by the plants of
the genus Taxus (yews). As their name suggests, taxanes
were first derived from natural sources, but now they
are all synthesized artificially. The two most commonly
used taxanes are paclitaxel and docetaxel. Although all
taxanes are currently used to treat patients with GECs,
only docetaxel has an FDA-approved indication for use
in combination with cisplatin and 5-FU to treat patients
with GECs. Paclitaxel and docetaxel both have therapeutic
indications for many solid tumor malignancies. However,
only docetaxel has an FDA-approved indication for the
treatment of advanced GECs. Paclitaxel has FDA-approved
indications as a single agent for second-line therapy for
metastatic ovarian cancer (12-16), for adjuvant treatment of
node-positive breast cancer (17), and for second-line therapy
for metastatic breast cancer (18), as well as for secondline
therapy for Kaposi’s sarcoma (19). In combination
with cisplatin, paclitaxel is also indicated as first-line
therapy for metastatic non-small cell lung (20) and ovarian
(21,22) cancers. Docetaxel was introduced at the end of
the 1990s; it was first approved in 1996 for the treatment of
refractory metastatic breast cancer (23-25). Additional FDA
indications for early breast cancers (26,27) and for advanced
non-small cell lung cancer (28,29), prostate cancer (30,31),
and metastatic head and neck cancers came later (32).
Paclitaxel
Paclitaxel was originally isolated from the bark of the
Pacific yew tree, Taxus brevifolia. Its chemical structure
was determined in 1971, and its mechanism of action was
elucidated in 1979 (33). Paclitaxel is an anti-microtubule
agent that irreversibly binds specifically to the subunit
of the protein tubulin and promotes the assembly of
microtubules. The stabilization of microtubules prevents normal mitotic spindle formation and function. This
disruption of normal spindle function, which is the primary
mechanism of action of paclitaxel (34,35) ultimately results
in chromosome breakage and inhibition of cell replication
and migration. Therefore, paclitaxel inhibits cell replication
by blocking cells in the late G2 and/or M phases of the
cell cycle(35). Another important mechanism of action of
paclitaxel includes induction of apoptosis via binding to
and subsequently blocking the function of the apoptosis
inhibitor-protein, bcl-2. Pharmacokinetics studies with
paclitaxel have demonstrated that its distribution is a
biphasic process, with values for α and β half-lives of
approximately 20 minutes and 6 hours, respectively (33).
True nonlinear pharmacokinetics may have important
clinical implications, particularly in regards to dose
modification, because a small increase in drug exposure
and hence toxicity (33). More than 90% of the time,
paclitaxel binds to plasma proteins. Approximately 71% of
an administered dose of paclitaxel is excreted in the stool
via the enterohepatic circulation (33). Renal clearance is
minimal, accounting for 14% of the administered dose(33).
In humans, paclitaxel is metabolized by cytochrome
P-450 (CP-450) mixed-function oxidases. Specifically,
either isoenzymes CYP2C8 and CYP3A4 of CP-450 will
metabolize paclitaxel to hydroxylated 3’ phydroxypaclitaxel
(minor) and 6α-hydroxyplacitaxel (major), as well as to
other forms of dihydroxylated metabolites. Paclitaxel is
typically administered intravenously at a dose of 135-175
mg/m2 every 21 days (33,36).
Docetaxel
While paclitaxel is a natural product, docetaxel is a semisynthetic
product. Docetaxel inhibits microtubule
disassembly and promotes microtubule stabilization,
leading to disruption of microtubule-mediated cellular
function during cell division, cell cycle arrest at G2/M
transition, and cell death (37). Like paclitaxel, docetaxel
induces the activation of several molecular pathways
leading to cellular apoptosis by disorganizing the
microtubule structure (38). However, another proposed
mechanism of action of docetaxel is related to its
effect on phospholipase-D (PLD) (38). PLD has been
implicated in several physiological processes, such as
membrane trafficking, cytoskeletal reorganization, cell
proliferation, differentiation, survival, and apoptosis (38).
Pharmacokinetics studies with docetaxel have demonstrated
a linear pharmacokinetic behavior with a 3-compartment
model. Docetaxel binds to plasma proteins more than 95%
of the time. Its metabolism also occurs via the CYP3A4
isoenzyme CP-450, and within 7 days of administration,
75% is eliminated in feces (38). Because most docetaxel is broken down in the liver, a reduced dose is recommended
for patients with hepatic dysfunction, particularly those
with elevated total bilirubin above the upper limit of normal
(ULN) or alkaline phosphatase greater than 2.5 times
ULN plus ALT and/or AST greater than 1.5 times ULN
(38). Renal impairment or age greater than 75 years are an
indication for docetaxel dose adjustment (38). Docetaxel
is typically administered intravenously at a dose of 60-100
mg/m2 every 21 days (33,39).
The most frequent dose-limiting toxicities (DLTs) of
both paclitaxel and docetaxel include myelosuppression,
hypersensitivity reactions, neuropathy, and musculoskeletal
effects. Myelosuppression is both dose- and scheduledependent,
but it is not cumulative, where neutropenia
is the principal DLT. The nadir of myelosuppression is
usually on the 8th-10th day and complete bone marrow
recovery is expected on the 15th-21th day (40). During
its early development and in the initial phase II studies,
docetaxel was administered at a dose of 100 mg/m2. In
these early studies, neutropenia reached its nadir on the 8th
day and resolved on the 15th-21st days of docetaxel infusion,
and febrile neutropenia requiring hospitalization was
observed in 10-14% of treated patients (38). Since its early
development, docetaxel is now administered at a modified
dose of 75 mg/m2. A significant reduction in febrile
neutropenia frequency was observed with this dose (38).
Taxane hypersensitivity reactions can be categorized
as type 1 (anaphylactoid) or type 2 (anaphylaxis).
Symptoms of an anaphylactoid reaction include dyspnea,
f lushing, chest pain and tachycardia, where the cause
is a surge of histamine release within 2-3 minutes after
the administration of the drug. Anaphylaxis is more
severe and can even be fatal; symptoms of anaphylaxis
include hypotension, angioedema, and urticaria. Both
types of reaction occur during the first two courses, and
typically begin during the first 15 minutes of the infusion
and resolve 15 minutes prior to the completion of the
infusion. Along with antihistamine premedication, the
administration of a prophylactic regimen consisting of 3-5
days of steroids beginning 1-2 days prior to treatment can
reduce the frequency and severity of a hypersensitivity
reaction (38,40). Once patients have experienced either
type of severe hypersensitivity reaction, the drug is further
contraindicated. Fortunately, the incidence of anaphylaxis
is low, occurring in only 2% of patients receiving paclitaxel
and in 13% of patients receiving docetaxel.
Peripheral neuropathy resulting from both axonal
degeneration and demyelination (40) is a DLT that is
dose-dependent and cumulative. Mild symptoms relating
to sensory loss usually improve or resolve completely
within several months after discontinuation of therapy. Pre-existing neuropathies are not a contraindication to
treatment. Central neurotoxicity may occur and may be
severe especially with paclitaxel. Myalgia and/or arthralgia
typically appear 2-3 days after drug administration, resolve
within a few days, and are unrelated to dose (41,42).
Docetaxel-associated neuropathy occurs less frequently
and with less severity than paclitaxel-associated neuropathy
(42).
Reversible fluid retention syndrome (42,43), which is
characterized by edema and third-space fluid retention,
is a unique side effect of docetaxel. Bowel wall edema
and pleural and peritoneal fluid retention are common
manifestations of this syndrome, which is caused by a
docetaxel-induced increase in capillary permeability.
The most serve end-organ complication of third-space
fluid collection is heart failure. This severe complication
can be ameliorated and prevented with prophylactic
administration of corticosteroids, along with aggressive and
early administration of diuretics (43).
No less important, but less frequently reported, toxicities
associated with ta xanes include fatigue, mucositis,
gastrointestinal symptoms, phlebitis, drug-induced
adult respiratory distress syndrome (for docetaxel),
and bradycardia plus swollen, red, painful mouth (for
paclitaxel). Fatigue is observed in 58-67% of the patients
treated with docetaxel, and it is occasionally severe enough
to cause a modification in dose (33). Mucositis typically
results from slow infusion, and it occurs more frequently
in patients treated with docetaxel than with paclitaxel.
Although less-severe gastrointestinal toxicityties, such as
nausea, vomiting, and diarrhea, also occur more frequently
with docetaxel, grade 3/4 gastrointestinal toxicities are
uncommon (42). Table 1 summarizes the rare adverse
effects associated taxanes.
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Clinical use of taxanes in the treatment/management of advanced gastroesophageal cancers
For many solid tumors, tumor responses and survival
outcomes are higher with CRT than with radiotherapy
(RT) alone (44-49). For patients with solid tumors, CRT is
used to palliate symptoms, treat definitively, and contribute
significantly to multimodality therapy. Chemotherapeutic
agents have been successfully used as radiosentisizers;
platinums, fluoropyrimidines, and taxanes are the most
commonly used chemotherapeutic agents.
The results of the Radiation Therapy Oncology Group
(RTOG) 85-01 trial (49) established that local disease
control and survival outcome were both improved with
CRT (RT combined with cisplatin and 5-FU) compared with RT alone. Therefore, most large randomized studies
of CRT in GECs have been designed with either 5-FU,
cisplatin, or both as radiosensitizers. Although taxanes are
used as part of CRT for GECs, their use as radiosensitizers
has been limited to phase II single-arm studies of patients
with both resectable and locally advanced (unresectable)
disease (50). Both paclitaxel and docetaxel are recognized
to be potent radiosensitizers, and their effectiveness in
GECs is demonstrated by the increased rates of curative
resection, cancer down-staging and pathologic complete
response (pCR) (51,52). Many single-institutions, as well
as cooperative, studies have suggested that taxane-based
CRT is feasible, tolerable, and efficacious in patients with
resectable GECs in either the preoperative or postoperative
setting (51,52). Preoperative paclitaxel-based CRT has
demonstrated promising rates of pathologic responses,
with observed pathCR rates of approximately 15-39%
(53-57). Similar promising outcomes have been observed
with preoperative docetaxel-based CRT (58-61).
However, most of the efficacy data on taxane-based CRT
come from small phase II studies because of what had
been established as standard of care chemotherapeutic
radiosensitizers by RTOG 85-01 (49). Results of the
CROSS (51) study highlight taxane-based CRT and
establish taxane-based CRT as a major contributor in a
large phase III pivotal clinical trial of GECs. Patients with
resectable esophageal cancer were randomly assigned to
paclitaxel and carboplatin plus concurrent RT followed
by surgery or to surgery alone. A total of 363 patients
with resectable (T2/3N0/1M0) esophageal and GEJ cancers
were enrolled. Preoperative CRT consisted of weekly
administrations of paclitaxel 50 mg/m2 and carboplatin
(AUC = 2) for 5 weeks and concurrent RT (41.4 Gy in 23
fractions, 5 days per week). Preoperative CRT did not
affect surgery rates (86% vs. 90%) or in-hospital mortality
rates (4% vs. 4%). However, R0 rates (92% vs. 65%) and
pathCR rates (33% vs. 0%) improved after completing
CRT. OS was significantly better (P = 0.011) in the
group of patients treated with CRT (hazard ratio [HR]
= 0.67; 95% confidence interval [95% CI], 0.50-0.92)
likely establishing a new standard of care for patients
with resectable GECs. The fact that the chemotherapy
regimen used for CRT in the CROSS study did not include
cisplatin and 5-FU is a significant departure from RTOG
85-01 (49).
The cytotoxic activity and survival benefit of both
paclitaxel and docetaxel have been demonstrated by many
pivotal phase III clinical studies, with each positive study
gaining these taxanes new FDA-approved indications
for use in many different malignancies. V-325 (11) is a
multi-institutional, international phase III study in which therapy-naïve patients with advanced or metastatic GC/
GEJ cancers were randomized to receive either docetaxel
(D) and cisplatin (C) plus 5-FU (DCF) or CF. Patients
in the treat arm received DCF (docetaxel 75 mg/m2 day 1,
cisplatin 75 mg/m2 day 1, plus infusional 5-FU 750 mg/
m2/24 hours days 1-5) intravenously every 3 weeks. The
primary end point was time to progression (TTP). A total
of 457 patients (DCF 227, CF 230) were treated. Ajani et
al. reported a more favorable TTP (5.6 vs. 3.7 months; HR
= 1.47 [95% CI, 1.19-1.82]; P = 0.001) and OS (9.2 vs. 8.6
months; HR = 1.29 [95% CI, 1.0-1.6]; P = 0.02) in patients
treated with DCF than with CF. Despite its promising
results, V-325 (11) was severely criticized for its moderate
toxicity; patients treated with DCF experienced more
neutropenia (82% vs. 57%) and febrile neutropenia (29%
vs. 12%) than those treated with CF. An ad hoc comparison
of patients’ benefits in terms of quality of life between the
two arms concluded that DCF significantly prolonged time
to definitive worsening of performance status versus CF
(median, 6.1 vs. 4.8 months; HR = 1.38 [95% CI, 1.08-1.76];
P = 0.009) (62,63). The results of this study led to FDA
approval of docetaxel for gastric and GEJ cancers, but every-
3-weeks DCF should be reserved for highly selected groups
of patients.
Because docetaxel was found to be an active agent in
GECs, many subsequent studies have offered modified
and alternative docetaxel combinations in order to reduce
toxicity and improve tolerance. In a randomized phase II study (64), Shah et al. observed moderate hematologic
toxicity with DCF despite primary prophylaxis with
growth colony-stimulating factor. Despite dose changes,
modified DCF was noted to be much better tolerated while
maintaining the same efficacy as its parent DCF.
In addition to dose and schedule modification of DCF
regimens, many other docetaxel-based chemotherapy
regimens have been evaluated. For instance, docetaxel has
been combined with irinotecan, oxaliplatin, and S-1. S-1
is not currently available outside of clinical trials in the
United States. The use of S-1 in advanced GECs in Western
countries had been tempered by the negative results of the
FLAGS (First Line therapy in Advanced Gastric cancer
Study) study (65), comparing cisplatin plus 5-FU to
cisplatin plus S-1.
Selecting between paclitaxel and docetaxel remains
an art rather than science. Though commonly practiced,
there are no convincing data in the medical literature on
GEC to support the interchangeability between docetaxel
and paclitaxel. In two randomized phase II studies (66,67)
from Asia comparing 5-FU combined with either paclitaxel
or docetaxel, no statistically significant difference in
therapeutic efficacy or survival outcomes was observed. It
remains unclear if there is a significant difference between
DCF (11) and ECF (68) or other standard regimens, or
between docetaxel triplet and doublets. Table 2 summarizes
selected randomized phase II or III stsudies with taxanebased
chemotherapy regimens as first-line therapy for metastatic GECs.
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Conclusion and future direction
Taxanes are a class of cytotoxic agents commonly
administered in patients with breast and lung cancers. Both
paclitaxel and docetaxel, two commonly used taxanes,
have many indications as both single agents as well as in
combination therapy for many solid tumors. They have also
been shown to contribute significantly to the management
of patients with both localized and advanced GECs. Direct
evidence for their use in the management of GECs is
derived from the results of several phase II studies. Phase III studies with taxanes in GECs are limited. V-325 (11)
and CROSS (51) are pivotal studies that not only changed
how we treat GECs, but also validated the role of taxanes in
the management of GECs. The V-325 (11) study is a pivotal
randomized study that demonstrated that docetaxelbased
chemotherapy improved TTP and OS in patients
with advanced GEC. The CROSS (51) study demonstrated
improvements in surgical outcomes and survival in
patients treated with preoperative CRT with paclitaxel
and carboplatin. Tables 2 and 3 summarize completed and
ongoing clinical trials with taxanes-base chemotherapy,
administered either alone or combined with targeted
therapy.
The future development of taxanes for use in GEC will
require establishing optimal taxane-based chemotherapy
regimens to fur ther develop with targeted therapy,
evaluating possible ways of overcoming mechanisms of
resistance to taxanes, and identifying molecular biomarkers
that are predictive of response. This effort will require the
collaborative efforts of many scientific disciplines.
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References
Cite this article as: Jimenez P, Pathak A, Phan A. The role of taxanes in the management of gastroesphageal
cancer. J Gastrointest Oncol. 2011;2(4):240-249. DOI:10.3978/j.issn.2078-6891.2011.027
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